Type 2 diabetes mellitus is a heterogeneous, polygenic disorder of metabolism [Matsuyama A et al. 2009]. The changes in life style pattern and behavior are associated with an increase incidence of type 2 diabetes. The disorder is affecting more than 90% of patients globally [Zimmet P Z et al. 2011, Jahan H et al. 2015].
The pathogenesis of type 2 diabetes involves inadequate secretion of insulin by pancreatic β-cell, and resistance in its action [Cavaghan M K et al. 2000]. The point in the progression of type 2 diabetes when pancreatic β-cells dysfunction emerges is less evident, so far. The proposed mechanisms involved in the dysfunction of beta-cell function include ER stress, glucolipotoxicity, and oxidative stress [Butler A E et al. 2003].
Currently available oral antidiabetic drugs include metformin and sulfonylureas. They play a pivotal role in the treatment of type 2 diabetic patients [Groop L C et al. 1992, Holman R R 2006].
Metformin suppresses glycogen break down and gluconeogenesis in the liver, and hence decreases basal glucose output. It also enhances muscles glucose metabolism in type 2 diabetic patients. However, the most worrisome complication associated with metformin treatment is lactic acidosis [Bodmer M et al. 2008].
Sulfonylureas are insulinotropic in their mechanism of action, and are found effective in majority of diabetic patients. However, few patients are found primary nonresponders to sulfonylureas treatment. In addition, chronic treatment with sulfonylureas may result in secondary failure to treatment [Pontiroli A E et al. 1994]. This may occurs as a result of multiple causes, involving (1) hyperstimulation of insulin producing beta-cells leading to desensitization; (2) persistent insulin secretion associated with the reduction of pancreatic insulin contents; and (3) hyperglycemia-induced beta-cells toxicity. The major concern associated with sulfonylureas treatment is symptomatic hypoglycemia due to sustained insulin release, irrespective of blood glucose levels [Matsuyama A et al. 2009, Pontiroli A E et al. 1994, Hosokawa Y A et al. 1997, Leahy J L 1996, Taverna et al. 2001, Kawaki J et al. 1999]. Moreover, treatment with sulfonylureas may also result in weight gain. It is therefore not the choice for treating obese patients [Bodmer M et al. 2008].
Despite intensive attempts towards long term management of type 2 diabetes, maintaining near euglycemic condition in these patients remains a challenge [Luna B et al. 2001].
Anthranilic acid and its derivatives are constituents of many bioactive molecules with a wide range of biological activities. Indeed, anthranilic acid nucleus serves as a biochemical precursor in the synthesis of amino acid tryptophan and its analogs, and also a major constituent of various alkaloids [Tiwari D et al. 2011, Syed M M et al. 1990]. Both experimental and preclinical studies demonstrated their medicinal properties, including matrix metalloproteinase inhibition, anticancer, anti-inflammatory, and analgesic activities (Syed M M et al. 1990, Cocco M T et al. 2004]. Therefore, the molecules based on anthranilic acid scaffold have gained much attention in drug discovery and development [Suleiman, M M et al. 2014, Thongtan J et al. 2006, DeLuca S et al. 2006].
Our most recent study identified the potential of 2,4-dinitroanilino-benzoic acid, an anthranilic acid derivative, as a novel antiglycating agent of the multiple stages of non-enzymatic glycation process (FIG. 1) [Choudhary M I. U.S. Pat. No. US9381182B2].
Keeping in view of the medicinal significance of anthranilic acid, the current study discovered the potential of anthranilic acid derivative, 2,4-dinotroanilino-benzoic acid (1), as an insulinotropic agent in the treatment of diabetes.